686-392 General Pathology “Immunopathology”ed.dent.psu.ac.th/oss/Upload/191.pdf · sompid/immunopath50 686-392 General Pathology “Immunopathology” Dr. Sompid Kintarak D.D.S.,

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686-392 General Pathology“Immunopathology”

Dr. Sompid Kintarak D.D.S., Ph.D.Department of StomatologyFaculty of Dentistry, PSU

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Content

• Immune cells• Cytokines• Major histocompatibility complex• Hypersensitivity reactions• Graft rejection• Immune tolerance• Autoimmune diseases• Amyloidosis

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Immune system

• Innate immunity• Adaptive immunity

• Humoral immunity• Cellular immunity

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Blood cells

1

2

34

5

1 Neutrophil

2 Lymphocyte

3 Monocyte

4 Eosinophil

5 Basophil

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T-lymphocyte• 60-70% of lymphocytes in

peripheral blood• TCR:CD3 complex• CD28 (binds costimulatory

molecules CD80 or CD86 on APC)

• CD4+ cell (MHC II)– Th1: IL-2, IFN- γ (cell-mediated

immunity)– Th2: IL-4, IL-5, IL-13 (B-cell

activation)

• CD8+ cell (MHC I)• CD4:CD8 ~ 2:1

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CD40L:CD40

B-lymphocyte• 10-20% of lymphocytes in

peripheral blood• CD19, CD20• MHC II, FcR, CD21

(receptor for complement, EBV)

• Differentiation to plasma cell and produce IgG, IgA, IgE (requires help from CD4+ T-cell)

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Macrophage

• Antigen-presenting cell

• MHC class II• Secrete IL-1, TNF-α

Dendritic cell

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Natural killer cell • 10-15% of lymphocytes in

peripheral blood• TCR-, CD3-• Innate immune system• Destroy virus, some

tumor cells• CD16, CD56

– CD16 is FcR for IgG(ADCC)

• Produce IFN-γ (recruit T lymphocytes)

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Immune response

CD40:CD40L

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Cytokines• Mediate innate immunity: IL-1, TNF-α, IL-6, type 1 IFN • Regulate lymphocyte proliferation and differentiation:

IL-2, IL-4, IL-5, IL-12, IL-15IL-10, TGF-ß down regulate immune response

• Activate inflammatory cells (mostly produced from T cells): IFN-γ, TNF-α, TNF-ß, migration inhibition factor

• Affect leukocyte movements (chemotaxis): IL-8, eotaxin, macrophage inflammatory protein-1α

• Stimulate hematopoiesis: colony-stimulating factors, IL-3, IL-7 (affect growth of lymphocyte progenitor cells)

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Major Histocompatibility Complex

• MHC class I: HLA-A, HLA-B, HLA-C– Presence on all nucleated cells and platelets

• MHC class II: HLA-DP, HLA-DQ, HLA-DR– Presence on APC, B cell

• MHC class III: C2, C3, Bf

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Major Histocompatibility Complex

• Organ transplantation• Induction of immune response• Regulation of immune response• Disease association

– HLA-B27 – ankylosing spondylitis– HLA-DR4 – rheumatoid arthritis– HLA-B12, B51, Cw7 – recurrence aphthous stomatitis– HLA-B5, B12, B27 – Behçet’s syndrome

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Immediate (Type I) hypersensitivity

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Arachidonic acid metabolites

Aspirin, indomethacininhibit

Arachidonic acid

Phospholipases x Steroids inhibitCell membrane phospholipids

Cyclooxygenase x

Vasodilation, Potentiate edema

(causes vasoconstriction, promotes plt aggregation)

(cause vasodilation, inhibits plt aggregation)

Prostaglandin G2

Prostaglandin H2

Prostacyclin, PGI2 Thromboxane A2 ,TXA2

PGD2 , PGE2 , PGF2α

5-Lipoxygenase

5-HPETE

Leukotriene A4,LTA4

LTC4

LTD4

LTE4

Vasoconstriction BronchospasmIncreased permeability

LTB4

(chemotaxis)

5-HETE 12-Lipoxygenase

Lipoxin A4 Lipoxin B4

Vasodilation Inhibit neutrophil chemotaxisStimulate monocyte adhesion

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Acute laryngeal edema caused by anaphylactic reaction to penicillin

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Antibody-mediated (Type II) hypersensitivity

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Complement activationAntigen-antibody (IgG or IgM)

complex

C1 Activated C1C4+C2

Classic pathway C3 convertase

Classic pathway C5 convertase

CLASSIC PATHWAY

ALTERNATIVE PATHWAY

C4b2a C4b2a3b

C3C3a

C5

C3 C3b C3bBb C3bBb3b

C5a

Microbial surfaces Polysaccharides Factor B

Factor DAlternative pathway

C3 convertasestabilized by

properdin

C5b C5-9C6 C7 C8 C9

Also generated via plasminor lysosomal proteases

Alternative pathway C5 convertase

C3b

C1 Activated C1

Mannose binding lectin

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The membrane attack complex:

RBC

Intact E. coli After incubation with complement

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Antibody-mediated (Type II) hypersensitivity

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Goodpasture’s syndrome: this is the even linear pattern of immunofluorescence with antibody to IgG (autoantibody) which is directed against the entire glomerular basement membrane (linear pattern).

From: www-medlib.med.utah.edu/WebPath/ From: Robbins and Cotran Pathologic basis of disease. 7th ed.

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Immune complex-mediated (Type III) hypersensitivity

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Hageman factor (XII)Plasmin, Kallikrein Collagen, basement membrane, activated plt

Prekallikerein activator (XIIa)

Vasodilation, Pain Vasc. Permeability

Fibrin split products

Prekallikrein

Kallikrein

Kininogen

KininFibrinopeptidesFibrinogen Fibrin +

Plasminogen Plasmin

XI XIa

Prothrombin Thrombin (IIa)

X Xa Acute inflammation

Vasc. Permeability, Chemotactic

PARs

C3 C3a

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Immune complex vasculitis

Vasculitis with fibrinoid necrosis

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Cell-mediated (Type IV) hypersensitivity• Delayed type hypersensitivity

– Granulomatous inflammation– Type I DM, multiple sclerosis– Contact dermatitis

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Delayed hypersensitivity in the skin

• Perivascularinfiltration by T cells and mononuclear phagocytes

• Anti-CD4 antibodies

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Formation of granuloma in cell-mediated (type IV) hypersensitivity

From: www-medlib.med.utah.edu/WebPath.html

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Contact dermatitis: pre-sensitized lymphocytes led to this inflammatory reaction a couple of days after contact with the offending plant material (poison oak and poison ivy).


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Graft rejection

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Hyperacute rejection of renal allograft: Preformed antibodies in the recipient's blood have attacked the endothelium in this transplanted kidney, leading to thrombosis with consequent widespread infarction of the renal cortex (note the characteristic pale appearance). The renal pelvis shows hemorrhagic infarction.

From: Robbins and Cotran Pathologic basis of disease. 7th ed.

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Acute rejection of renal allograft: The cortex is thickened and pale tan due to an intense infiltrate of predominantly mononuclear cells. Compare with the previous image. The mononuclear inflammatory infiltrate on the right of the image represents acute cellular rejection. The thrombosed vessel and consequent infarction with typical coagulative necrosis are manifestations of acute humoral rejection.


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Chronic rejection of renal allograft: The kidney is shrunken with a greyish irregular surface, indicating scarring. This is due predominantly to chronic vascular injury, resulting in atrophy and fibrosis of the renal parenchyma.


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Acute vascular rejection in heart transplant. The inflammatory reaction consists mostly of lymphocytes and is seen manly around small arteries, a vasculitis.


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By immunofluorescence, antibody to IgG is seen highlighting the vascular walls in this heart with acute vascular rejection.


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Chronic vascular rejection in renal transplant: a renal biopsy shows marked interstitial fibrosis.


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The renal arteries with chronic vascular rejection are markedly thickened and fibrotic.


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Acute cellular rejection in heart transplant: T-lymphocytes are identified by immunoperoxidase staining with antibody to CD3.


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GVHD: Besides the icterus in this skin there is a fine scaling rash in this patient following bone marrow transplantation with a 5 out of 6 antigen match. An example of GHVD in which donor lymphocytes attack host tissues.


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GVHD: There is vacuolization and dissolution of epidermal cells along the basal layer, along with lymphocytes. At the arrow is a rounded pink apoptotic body.


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GVHD: marked cholestasis in the liver, seen here as large collections of yellow-green bile pigment in the bile canaliculi.


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GVHD: there are yellow-brown collections of bile in the canaliculi, as well as chronic inflammatory cells within the liver parenchyma.


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Autoimmune disease


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Mechanisms of autoimmune diseases

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Systemic lupus erythematosus (SLE)

• Causes: unknown– Genetic predisposition– Exogenous factors: drug (procainamide, hydralazine,

isoniazid, D-penicillamine), UV, hormone (estrogen)• Failure to maintain self tolerance with activation

of B cell• Tissue damage caused by immune complex

(type 3 hypersensitivity) and antibody-mediated injury (type 2 hypersensitivity)

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SLE: malar/butterfly rash over the face, the rashes are made worse by sun exposure.


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LE cell test: the pink blobs are denatured nuclei (here are two). One is seen being phagocytozed in the center by a PMN. This test is not nearly as sensitive as the ANA which has supplanted the LE cell test. Therefore, NEVER order an LE cell test.


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ANA test: homogenous or diffuse, rim or peripheral, speckled, and nucleolar pattern.


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ANA test: double stranded DNA. These little Crithidiaorganisms have a small kinetoplast between the nucleus and the flagella which glows bright green under immuno-fluorescence microscopy, and is indicative of anti-native DNA antibody that is very specific for SLE.


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Skin biopsy: the region of rash reveals liquefactive necrosis of the basal layer at the dermal-epidermal junction along with dermal chronic inflammatory cell infiltrates (often perivascular) and extravasation of red blood cells (purpura) leading to the visible rash.


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Skin biopsy: the region of rash reveals liquefactivenecrosis of the basal layer at the dermal-epidermal junction along with edema.

Immunofluorescence: IgGdeposits along the dermal-epidermal junction.

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Immunofluorescence of skin with antibody to IgG shows a band-like deposition of immune complexes that is bright green at the dermal epidermal junction in this skin biopsy taken from an area with a visible rash. With SLE such deposition can be found in skin uninvolved by a rash, whereas with DLE the immune complexes are found only in involved skin.


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SLE: Vasculitis with chronic inflammatory cells


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SLE: shown here is Libman Sacks endocarditis in which there are many flat, reddish-tan vegetations spreading over the mitral valve and chordae.


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Lupus nephritis in SLE: a glomerulus with thickened pink capillary loops, the so-called “wire loops”. The surrounding renal tubules are unremarkable.


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A granular pattern of immunofluorescence in the glomerulus with antibody to IgG, indicative of deposition of immune complexes in the basement membranes of the glomerular capillary loops (lumpy-bumpy pattern).


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Granular pattern of immunofluorescence in the glomeruluswith antibody to C1q complement, which is more specific for SLE


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SLE: the thickened basement membrane (arrow) that results from immune complex deposition in the glomerularcapillary loop is prominent in this electron micrograph


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Rheumatoid arthritis• Autoimmune disease• A chronic systemic inflammatory disorder that may affect

many tissues and organs, but principally attacks the joints, producing a nonsupurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints.

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Immunopathogenesis of rheumatoid arthritis

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• Associated with MHC Class II• HLA-DR4 (risk 4-6 times)• Rheumatoid factor (RF) – most IgM• Autoantibody to Fc portion of IgG• Positive 60-90% of RA, SLE, SS

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Rheumatoid arthritis

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Sjögren syndrome• Dry eyes and dry mouth

resulting from immune mediated lacrimal and salivary gland destruction (lymphocytic infiltration and fibrosis)

• 40% occur in isolation (primary form)

• 60% occur in association with other autoimmune diseases (secondary form)

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Sjögren syndrome

• 75% of patients have RF• 50-80% of patients have ANAs

– Ribonucleoprotein antigens: SS-A and SS-B • HLA-B8, HLA-DR3, DRW52 related with primary

SS• Commonly in older women, ages 50-60 y• 40 times risk of developing lymphoid

malignancies esp. NHL (marginal zone lymphoma)

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Sjögren syndrome: the mononuclear inflammatory infiltrates, interstitial fibrosis, and acinar atrophy of a minor salivary gland in a biopsy of lip is typical for long-standing Sjögren syndrome.

From: Neville Damm Allen Bouquot. Oral & Maxillofacial Pathology, 2nd ed.

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Systemic sclerosis

• Abnormal accumulation of fibrous tissue in the skin and multiple organs

• Excessive fibrosis triggered from abnormal immune responses and vascular damage

• Diffuse vs Limited scleroderma• CREST syndrome (calcinosis, Raynaud

phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia)– Anticentromere antibody

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A patient demonstrating the taut and shiny skin typical of sclerodactyly. The skin becomes inelastic and it is hard to move the fingers.


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A higher magnification of the taut, shiny, inelastic skin with sclerodactyly. Note also the cheilosis at the corners of the mouth from riboflavin deficiency as a result of the malabsorption that can occur with scleroderma.


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A, Normal skin. B, Skin biopsy from a patient with systemic sclerosis. Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages (e.g. hair follicles) and foci of inflammation (arrow).

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At low magnification, the collagen of the dermis is increased. Chronic inflammatory cells are sparse with systemic sclerosis, unlike SLE.


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At high magnification, the dermis is expanded by dense collagenous fibrosis in a patient with systemic sclerosis. Immunofluorescence is not helpful with scleroderma.


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This trichrome stain of the stomach demonstrates intense blue staining in the submucosa from the collagen deposition. Such fibrosis can occur anywhere in the GI tract, but is most common in the lower esophagus, leading to the esophageal dysmotilitywith systemic sclerosis.

Epithelium

Muscle

Fibrosis


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Renal disease suggests diffuse scleroderma in this patient with hyperplastic arteriolosclerosis and malignant hypertension (blood pressure 300/150 mm Hg)


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Immunologic deficiency syndrome

• Primary immunodeficiencies– genetic

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Immunologic deficiency syndrome

• Secondary immunodeficiencies – arise as complications of infections; malnutrition; aging; or side effects of immunosuppression, irradiation, or chemotherapy for cancer and other autoimmune diseases

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Amyloidosis

• Primary amyloidosis – association with some immunocyte dyscrasia, multiple myeloma

• Secondary amyloidosis – occurs as a complication of an underlying chronic inflammatory or tissue destructive process

• Hereditary or familial amyloidosis

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Amyloidosis is characterized by slow deposition over years of increasing amounts of an amorphous proteinaceousmaterial in one or more tissues. Seen here in the heart between the darker red myofibers are pale pink amyloiddeposits.


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With conge red stain and observed under polarized light, the amyloid has a characteristic “apple green’ birefringence as seen here in a deposit around an artery in the heart.


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By electron micrograph, amyloid is composed of a “beta-pleated sheet” of fibrils, seen here as irregular grey material. When the amyloid protein is made up of immunoglobulin light chains, then it is “AL amyloid” and when it is derived from serum amyloid-associated protein, then it is “AA amylod.” in terms of the effect upon the organs, “amyloid is amyloid”.


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This is the immunofluorescent appearance of the myocardium with antibody to lambda light chain. Thus, this is “AL amyloid”.


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References• Abbas AK, Chapter 6: Diseases of immunity. In: Kumar V, Abbas

AK, Fausto N (eds). Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: WB Saunders Co. 2005. p. 193-267. and p. 1305-1309.

• Kumar V, Cotran RS, Robbins SL (eds). Basic pathology. 6th ed. Philadelphia: WB Saunders Co. 1997. p. 81-131.

• Peakman M, Vergani D (eds). Basic and clinical immunology. New York: Churchill Livingstone. 1997.

• Cotran RS, Kumar V, Robbins SL (eds). Robbins pathologic basis of disease. 5th ed. Philadelphia: WB Saunders Co. 1994. p. 171-240.

• www-medlib.med.utah.edu/WebPath/ TUTORIAL/TUTORIAL.html

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Documents

686-392 General Pathology “Immunopathology”ed.dent.psu.ac.th/oss/Upload/191.pdf · sompid/immunopath50 686-392 General Pathology “Immunopathology” Dr. Sompid Kintarak D.D.S.,